Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:10]1[O:32][C@H:31]([CH2:33][O:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@:11]1([CH3:43])[O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)C1C=CC=CC=1.[NH2:44][C:45]1[N:53]=[C:52]2[C:48]([NH:49][CH:50]=[N:51]2)=[C:47]([Cl:54])[N:46]=1.N12CCCC=C1CCCCN2.FC(F)(F)S(OC[Si](C)(C)C)(=O)=O>C(#N)C>[NH2:44][C:45]1[N:53]=[C:52]2[C:48]([N:49]=[CH:50][N:51]2[C@@H:10]2[O:32][C@H:31]([CH2:33][O:34][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:21]([O:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@:11]2([CH3:43])[O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:47]([Cl:54])[N:46]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: C[C@]1(OC(=O)c2ccccc2)C(OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C1=C2CCCCNN2CCC1
Agent: C[Si](C)(C)COS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Temperature: 65 °C

Procedure:
To a pre-cooled solution of 1,2,3,5-tetra-O-benzoyl-2-C-methyl-D-ribofuranose [Harry-O'kuru, Rogers E.; Smith, Jennifer M.; Wolfe, Michael S, “A Short, Flexible Route toward 2′-C-Branched Ribonucleosides,” J. Org. Chem., 62:1754-1759 (1997)] (1.74 g, 3.00 mmol) in acetonitrile (15 mL) was added 2-amino-6-chloropurine (0.56 g, 3.30 mmol), then diazabicyclo[5.4.0]undec-7-ene (DBU) (1.37 g, 9.00 mmol), and then dropwise trimethylsilylmethyl trifluoromethanesulfonate (TMS trifate) (2.67 g, 12.00 mmol). The resulting mixture was heated to 65° C. for 4 h, then cooled and partitioned between saturated aqueous sodium bicarbonate (200 mL) and dichloromethane (200 mL). The organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude product was used directly in step B.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH2:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]([F:38])([F:37])[C:27]1[N:31]2[CH2:32][CH2:33][NH:34][C:35](=S)[C:30]2=[N:29][N:28]=1.CO>C(OCC)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10](=[O:11])[NH:12][NH:13][C:35]1[C:30]2[N:31]([C:27]([C:26]([F:38])([F:37])[F:25])=[N:28][N:29]=2)[CH2:32][CH2:33][N:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Reactant: FC(F)(F)c1nnc2n1CCNC2=S
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NNC1=NCCn2c1nnc2C(F)(F)F)Cc1cc(F)c(F)cc1F

Procedure:
A mixture of 207 mg (0.6 mmol) of tert-butyl[(1R)-3-hydrazino-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (Intermediate 4), 110 mg (0.5 mmol) of 3-(trifluoromethyl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrazine-8(5H)-thione (Intermediate 6), and 5.5 mL of methanol was stirred at reflux for 1 day. Diethyl ether was added to the cooled solution, resulting in precipitation. The solid was removed by filtration, and the filtrate was concentrated to dryness. Purification of the residue by preparative HPLC (C18 reverse phase column, 30-80% acetonitrile in water containing 0.05% trifluoroacetic acid) afforded the title compound. LC-MS 536 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1.[NH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:28][CH:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:24])=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1
Reactant: NC1CCOCC1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Product: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NC3CCOCC3)cn2)cn1
Yield: 73 %

Procedure:
As described for example 43c, 6-(4-(1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (46 mg, 0.126 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (41 mg, 73%) which was obtained as a white foam after purification by chromatography (silica, 0-10% methanol in dichloromethane). MS: m/e=448.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[N:16]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][C:24]#[N:25])[CH2:19][CH2:18]3)[C:8]3=[C:9]4[S:15][CH:14]=[CH:13][C:10]4=[N:11][CH:12]=[C:7]3[N:6]=2)[CH2:2]1.O1CCC[CH2:27]1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(#N)C>[CH3:27][N:1]1[CH2:4][CH:3]([C:5]2[N:16]([C@H:17]3[CH2:18][CH2:19][C@H:20]([CH2:23][C:24]#[N:25])[CH2:21][CH2:22]3)[C:8]3=[C:9]4[S:15][CH:14]=[CH:13][C:10]4=[N:11][CH:12]=[C:7]3[N:6]=2)[CH2:2]1
Reactant: C1CCOC1
Reactant: N#CC[C@H]1CC[C@H](n2c(C3CNC3)nc3cnc4ccsc4c32)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CN1CC(c2nc3cnc4ccsc4c3n2[C@H]2CC[C@H](CC#N)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [trans-4-(2-azetidin-3-yl-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)cyclohexyl]acetonitrile (14 mg, 0.038 mmol) in methanol (0.5 mL)/tetrahydrofuran (0.5 mL)/acetonitrile (0.5 mL) was added 37% aq. formaldehyde solution (12 μL, 0.16 mmol). The resulting mixture was stirred at room temperature for 10 min before sodium triacetoxyborohydride (16 mg, 0.077 mmol) was added. The mixture was stirred at room temperature for 1 h and then diluted with MeOH and purified by prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.8 mg, 6%). LCMS calculated for C20H24N5S (M+H)+: m/z=366.2. Found: 366.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:17]([OH:19])=O)[CH:3]=1.S(Cl)([Cl:22])=O.CN(C)C=O.CN(C1C=CC=CN=1)C>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:17]([Cl:22])=[O:19])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(-c2nc(C(=O)O)cc(Cl)c2Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(-c2nc(C(=O)Cl)cc(Cl)c2Cl)cc1
Temperature: 80 °C

Procedure:
To a mixture of 4,5-dichloro-6-(4-methoxyphenyl)-picolinic acid (4.50 g, 15.1 mmol) in toluene (40 mL) was added thionyl chloride (1.65 mL, 22.6 mmol) and dimethylformamide (0.06 mL, 0.8 mmol). Reaction mixture was heated at 80° C. for 12 h. HPLC analysis of an aliquot treated with methanol and dimethylaminopyridine indicated complete conversion of the starting material. Reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to provide a yellow solid. Toluene (40 mL) was added to dissolve the solid and concentrated under reduced pressure and then this process was performed a second time. 4,5-Dichloro-6-(4-methoxyphenyl)-picolinoyl chloride was isolated as a yellow solid (4.64 g, 97% yield). 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.85-7.77 (m, 2H), 7.06-6.98 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 168.91, 161.06, 158.35, 146.26, 145.13, 133.92, 131.35, 129.16, 124.13, 113.70, LRMS. Calcd. for C13H8Cl3NO2: 314.96. Found: m/z=253 (M+-COCl), 218.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[CH:21][C:20]=1[CH3:30])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[CH:21][C:20]=3[CH3:30])[CH3:18])=[O:15])[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Reactant: Cc1cc(C(C)(C)C#N)ccc1C(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(C(C)(C)C#N)ccc1C(C)NC(=O)Cn1cnc2cccc(C#N)c21
Yield: 43.1 %

Procedure:
To a solution of (7-cyano-1H-benzimidazol-1-yl)acetic acid (250 mg, 1.24 mmol) prepared according to scheme 3, 2-[4-(1-aminoethyl)-3-methylphenyl]-2-methylpropanenitrile (251 mg 1.24 mmol) prepared according to scheme 15 and DMAP (150 mg, 1.24 mmol) stirred in anhydrous DMF (4.0 mL) is added HATU (473 mg, 1.24 mmol) after 18 hours of stirring, the mixture is diluted with Methanol (200 μL) the solution is purified directly on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4 N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product 2-(7-cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-2-methylphenyl]ethyl}acetamide (206 mg, 43%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.45 (d, J=6.84 Hz, 3H) 1.66 (s, 6H) 2.37 (s, 3H) 5.20 (q, J=6.84 Hz, 1H) 5.30 (s, 2H) 7.25 (d, J=1.95 Hz, 1H) 7.32 (dd, J=8.20, 2.15 Hz, 1H) 7.38 (dd, J=8.11, 7.71 Hz, 1H) 7.44 (d, J=8.20 Hz, 1H) 7.67 (dd, J=7.42, 0.78 Hz, 1H) 7.96 (dd, J=8.20, 0.98 Hz, 1H) 8.24 (s, 1H), MS [M+H], calcd: 386.2. found: 386.2.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[CH3:3].[H-].[Na+].[H][H].[CH3:14]I>O1CCCC1>[CH3:14][O:1][CH:2]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(O)c1ccncc1
Reactant: CI
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)c1ccncc1

Procedure:
A solution of 8.4 g (0.068 mol) of 4-(1-hydroxyethyl)pyridine in 20 ml of absolute tetrahydrofuran is added dropwise to a suspension of 2 g (0.083 mol) of sodium hydride (3.3 g of 60% oil dispersion; washed in toluene) in 80 ml of absolute tetrahydrofuran. After the development of hydrogen has ceased, 23 g (0.16 mol) of methyliodide are added at 18°-20° C. and the mixture is left to react for 2 hours. The reaction mixture is concentrated by evaporation, the residue is combined with 40% aqueous potassium carbonate solution and extracted with ether. The organic phase is separated, dried over sodium sulphate and concentrated by evaporation. After distillation of the crude product at 82°-85° C./20 mbar, 5.2 g (55.6% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:22](Cl)=[O:23].C(N(CC)CC)C>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:22]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6])=[O:23]
Reactant: COc1ccc(Br)c(C(=O)Cl)c1
Reactant: COC(=O)c1ccc(C)c(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(OC)ccc2Br)c1
Yield: 73.7 %

Procedure:
Methyl 3-amino-4-methylbenzoate (3.18 g), 2-bromo-5-methoxybenzene-1-carbonyl chloride (4.8 g) and triethylamine (5.4 ml) in THF (45 ml) were stirred at room temperature for 2.5 hour and then concentrated. The residue was dissolved in ethyl acetate and washed with 1N HCl, water, brine, dried (magnesium sulfate) and concentrated. The residue was recrystallised from hot ethyl acetate, washed with ether, and air dried to yield methyl 3-[(2-bromo-5-methoxybenzoyl)amino]-4-methylbenzoate as a white solid (5.36 g); NMR Spectrum: (DMSOd6) 2.39 (s, 3H), 3.83 (s, 3H), 3.87 (s, 3H), 7.02 (m, 1H), 7.23 (d, 1H), 7.42 (d, 1H), 7.60 (d, 1H), 7.75 (m, 1H), 8.12 (s, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 377.
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[CH:17][CH:18]=1)[N:8]=[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[N:10]=2.C(N(CC)CC)C.Cl[C:27]1[N:36]=[C:35]([NH:37][CH3:38])[C:34]2[C:29](=[CH:30][C:31]([O:41][CH3:42])=[C:32]([O:39][CH3:40])[CH:33]=2)[N:28]=1>C(O)CCC>[N:8]1[C:7]2=[CH:17][CH:18]=[CH:3][CH:4]=[CH:5][C:6]2=[N:10][C:9]=1[N:11]1[CH2:16][CH2:15][N:14]([C:27]2[N:36]=[C:35]([NH:37][CH3:38])[C:34]3[C:29](=[CH:30][C:31]([O:41][CH3:42])=[C:32]([O:39][CH3:40])[CH:33]=3)[N:28]=2)[CH2:13][CH2:12]1
Reactant: CNc1nc(Cl)nc2cc(OC)c(OC)cc12
Reactant: Clc1ccc2nc(N3CCNCC3)nc-2cc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CNc1nc(N2CCN(c3nc4cccccc-4n3)CC2)nc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
A mixture of 2-(1-piperazinyl)cycloheptimidazole hydrocloride (1.5 g, described in Example 1) and triethylamine (1.0 g) in butanol (150 ml) was stirred at room temperature for 15 min and 2-chloro-4-methylamino-6,7-dimethoxyquinazoline (1.53 g) was added. The mixture was refluxed for 22 hr, cooled and filtered. The precipitate was washed and dried to give 2.18 g of the title compound. This compound was dissolved in methanol and the solution was acidified with hydrogen chloride. The precipitate was collected, washed with diethyl ether and crystallized from water-methanol to obtain the dihydrochloride salt of the title compound: mp>250° C.; ir (nujol mull) 3000 cm-1 ; uv max (MeOH) 345 (ε=22,000), 257 nm (ε=54,500) and 245 nm (ε=55,200); nmr (DMSO-d6) δ 3.07 (d, 3H), 3.88 (s, 6H), 4.18 (s, 8H) and 8.0 (s, 7H); and Anal. Calcd for C23H25N7O2.2HCl. 1/2 H2O: C, 53.90% H, 5.46% N, 19.14% Cl, 13.86% and Found: C, 53.82% H, 5.68% N, 19.47% Cl, 13.1%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:13])=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)[CH3:2].C(O)(=[O:16])C.OO>O1CCCC1>[CH2:1]([O:3][C:4]1[C:5]([F:13])=[C:6]([OH:16])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(B(O)O)c1F
Reactant: CC(=O)O
Agent: OO
Solvent: C1CCOC1
Product: CCOc1cccc(O)c1F
Reaction time: 23 h
Yield: 71 %

Procedure:
To a solution of 3-ethoxy-2-fluoro-phenylboronic acid (10.0 g, 0.054 mol) in tetrahydrofuran (150 mL) was added glacial acetic acid (60 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 8 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 23 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated to give 3-ethoxy-2-fluoro-phenol (6.00 g, 71%) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OCC)C.CC(N=NC(C#N)(C)C)(C#N)C>[Br:21][CH2:13][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1ccc(CBr)cc1OC
Yield: 70.2 %

Procedure:
To a solution of methyl 2-methoxy-4-methylbenzoate (10.00 g, 55 mmol) in CCl4 (150 mL) were added NBS (11.8 g, 66 mmol) and AIBN (0.100 g). The reaction mixture was refluxed for 18 h. The reaction mass was diluted with diethyl ether and washed with 25% NaOH solution. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 10.00 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.77 (m, 6H), 4.68 (s, 2H), 7.06 (d, J=7.8 Hz, 1H), 7.23 (s, 1H), 7.61 (d, J=7.8 Hz, 1H); MS (m/z): 259.13 (M)+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH:26]=O>>[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: Cn1cccc1C=O
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Cn1cccc1CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1-methylpyrrole-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(1-methylpyrrol-2-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C(N(CCC)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]3[NH:23][CH:24]=[CH:25][N:26]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)CC.[CH3:31][C:32]1[N:37]=[C:36]([CH:38]=O)[CH:35]=[CH:34][CH:33]=1.[C:40]([BH3-])#[N:41].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:6]([N:41]([CH2:40][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:27])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:21][C:22]3[NH:26][CH:25]=[CH:24][N:23]=3)[CH2:38][C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:31])[N:37]=3)=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)[CH2:7][CH2:8][CH3:9])[CH2:5][CH3:10]
Reactant: CCCN(CCC)c1ccc(NC(=O)c2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: [BH3-]C#N
Reactant: Cc1cccc(C=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3cccc(C)n3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (104.9 mg) obtained in Example 47-3 was dissolved in methanol (3.2 ml) and then added with 6-methylpyridine-2-carboxaldehyde (36.3 mg) and sodium cyanoborohydride (31.4 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, a 1 mol/l sodium hydroxide aqueous solution was added to the reaction solution, followed by separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and then treated with hydrochloric acid, thereby obtaining hydrochloride (75.9 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[CH3:21]O>>[CH3:21][O:15][C:14](=[O:16])[CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CO
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCNC(=O)OCc1ccccc1

Procedure:
Prepared by the procedure described in Example 1, Step A from N-CBZ-β-alanine (5 g, 22.4 mmole), methanol and thionyl chloride to give the title compound. ##STR95##
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:16]=3)[CH:9]=2)[N:4]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:3]=1.[F:34][C:35]1[CH:36]=[C:37]([CH:55]=[C:56]([F:58])[CH:57]=1)[CH2:38][N:39]1[C:43]([CH3:44])=[C:42](B2OC(C)(C)C(C)(C)O2)[C:41]([CH3:54])=[N:40]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[F:34][C:35]1[CH:36]=[C:37]([CH:55]=[C:56]([F:58])[CH:57]=1)[CH2:38][N:39]1[C:43]([CH3:44])=[C:42]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:16]=4)[CH:9]=3)[N:4]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:3]=2)[C:41]([CH3:54])=[N:40]1
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cc(F)cc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 113.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, N-(5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)methanesulfonamide (Intermediate 23) (160 mg, 0.267 mmol) was coupled with 1-(3,5-difluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 24) (111.89 mg, 0.321 mmol) in sodium carbonate (84.89 mg, 0.801 mmol) Pd(PPh3)2Cl2 (9.7 mg, 0.013), Toluene/ethanol/water (7/7/2 mL) to afford 210 mg of the crude compound. MS: m/z=692.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]([C:20]1[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]2[C:23]([CH:24]3[CH2:34][CH:25]3[CH2:26][O:27]2)=[CH:22][CH:21]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1/[CH:16]=[CH:17]\[CH2:18]O)(=[O:8])=[O:7])=[O:4].BrC1C=C(F)C=CC=1S(N(C1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1)[C:47](OC)=[O:48])(=O)=O>>[CH3:1][O:2][C:3]([N:5]([C:20]1[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]2[C:23]([CH:24]3[CH2:34][CH:25]3[CH2:26][O:27]2)=[CH:22][CH:21]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1/[CH:16]=[CH:17]\[CH2:18][CH2:47][OH:48])(=[O:7])=[O:8])=[O:4]
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCC1CC21
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CCO)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 64, starting from methyl (1aRS,7bSR)-5-[N-(2-bromo-4-fluorobenzenesulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 65) and (Z)-4-tributylstannanylprop-3-en-1-ol (prepared according to Miura et al, Organic Letters, 2005, 7(3) 503).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:16])[C:14](I)=[C:10]2[N:9]=[C:8]([CH3:17])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[Cl:18][C:19]1[S:20][CH:21]=[C:22]([Cl:24])[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.CC1OCCC1>CC(N(C)C)=O>[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:16])[C:14]([C:21]3[S:20][C:19]([Cl:18])=[N:23][C:22]=3[Cl:24])=[C:10]2[N:9]=[C:8]([CH3:17])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nc2c(I)c(C)nn12
Reactant: Clc1csc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CC1CCCO1
Solvent: CC(=O)N(C)C
Product: CCC(CC)c1cc(C)nc2c(-c3sc(Cl)nc3Cl)c(C)nn12
Temperature: 70 °C
Yield: 87.3 %

Procedure:
7-(1-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (10 g, 29.17 mmoles), 2,4-dichlorothiazole (5.2 g, 33.76 mmoles), cesium carbonate (19.9 g, 61.07 mmoles) and 1,10-phenanthroline (1 g, 5.5 mmoles) are charged into a 250 mL 3-necked round bottomed flask, followed by 2-MeTHF (36 mL, 3.6 volumes). The reaction mixture is degassed with nitrogen and then evacuated. Cuprous chloride (0.57 g, 5.7 mmoles), DMAC (10 mL, 1 volume) and 2-MeTHF (4 mL, 0.4 volumes) are added in succession. The reaction mixture is degassed with nitrogen and then evacuated. The contents are refluxed for 20 hr. The reaction mixture is cooled to ˜70° C. and 2-MeTHF (100 mL, 10 volumes) is added. The contents are filtered at ˜70° C. and the residual cake is washed with 2-MeTHF (80 mL, 8 volumes) at about 65-72° C. The filtrate is transferred into a separatory funnel and extracted with water. The organic layer is separated and washed with dilute HCl. The resulting organic layer is treated with Darco G60, filtered hot (60° C.). The filtrate is concentrated at atmospheric pressure to ˜2.8 volumes. 25 mL 2-propanol is added, followed by re-concentration to ˜2.8 volumes. An additional 25 mL 2-propanol is added, followed again by re-concentration to ˜2.8 volumes. Finally, 48 mL 2-propanol is added. The contents are cooled to −7° C., maintained at −7° C. for 1 hr., filtered and rinsed with 20 mL chilled 2-propanol. Product is suction dried and then vacuum dried at 60° C. to afford 9.41 g 7-(1-ethyl-propyl)-3-(2,4-dichloro-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (purity of product by HPLC assay is 95.88%). MS (ES)=369 (M+1).